UPDATES IN DM AND CKD MANAGEMENT: "ARE SGLT2 INHIBITORS THE ANSWER?

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https://doi.org/10.33591/sfp.47.8.u1

Unit No. 1
ARE OUR TYPE 2 DIABETES PATIENTS SUFFICIENTLY PROTECTED FROM CARDIORENAL
COMPLICATIONS?
A/Prof Goh Su-Yen

ABSTRACT inhibitors was still under 20 percent in 2019 (from an initial

Cardiovascular and renal outcome trials categorically 0.2 percent in 2014 when the drug class was introduced
demonstrate the benefits of SGLT2 inhibitors in Singapore). With 82 percent of the registry patients
(SGLT2i). Various pharmacotherapy algorithms
recommend early use of SGLT2i, especially among
having eGFR >45ml/min/1.73m2 (current on-label
those with existing cardiovascular disease, heart eGFR recommendation), one would nonetheless expect a
failure, or kidney disease. Despite a widening substantially higher prescribing rate.
spectrum of patient eligibility, treatment gaps and
clinical inertia still exist. Similar sentiments of clinical inertia echo across the globe,4
calling for a concerted shift from linear treatment algorithms
KEYWORDS: Cardiorenal, SGLT2 inhibitor. based on a HbA1c target setting to parallel, independent
considerations of atherosclerotic cardiovascular disease,
SFP2021; 47(8) : 5-8 heart failure, and renal risks.

ACCELERATE TRANSLATION FROM TRIALS

ARTICLE TO CLINICAL PRACTICE

The sociological concept of diffusion of innovation1 can be CVOTs with SGLT2 inhibitors showed a consistent risk
applied in medicine. It is easy to draw parallels: innovators reduction of approximately 30 percent for hospitalisation
are the researchers, early adopters are the early implementers for heart failure (HF), and SGLT2 inhibitors had a great
in clinical settings, and those who are a little slower off the potential to be effective for prevention of HF in a wide
blocks often argue that a robust evidence base must exist or variety of type 2 diabetes (T2D) patients independent of
else risk violating Primum Non Nocere. their history of HF or cardiovascular disease (CVD).
Wherever we as individuals may fall in Everett Roger’s Restricted inclusion criteria in the initial CVOTs may limit
continuum, we owe it to our patients to keep up with the generalisability to real-world people with T2D, especially
literature and critically appraise studies as data emerges. those at the low end of the CV and renal risk spectrum.
As a clinical community, we should improve both early In most countries, SGLT2 inhibitors are not currently
implementation of effective therapy as well as de-adoption prescribed in patients with eGFR <45 mL/min/1.73 m2,
of interventions that lack value. limiting the possibility of extending these observations to
a T2D population at higher renal risk. Locally, on-label
TREATMENT GAP EXISTS prescribing at the time of press is as follows:

Contrary to a wealth of evidence from cardiovascular Dapagliflozin Empagliflozin Canagliflozin

outcome trials (CVOTs), and despite updates to clinical eGFR limit for indication (ml/min/1.73m2 )
guidelines that prioritise SGLT2 inhibitor usage, adoption Type 2 >45 >45 >45
and implementation in daily real-life clinical practice is diabetes
lagging.2 By contrast, other classes of oral agents remain Heart >30 Not HSA Not HSA
more widely used despite a lack of evidence of cardio- failure approved approved
renal benefits and similar or even higher pill costs. In a with
local diabetes registry3 of more than 120,000 patients reduced
across primary and specialist care, the utilisation of SGLT2 ejection
fraction
(HFrEF)
Diabetes Pending HSA Not HSA >30
GOH SU-YEN kidney review approved
Associate Professor disease (>25)
Head, SingHealth Duke Diabetes Centre The CREDENCE trial,5 released in 2019, involved
Clinical Director, Future Health Systems patients with DKD, eGFR 30 to 90 ml/min/1.73 m2, and
Senior Consultant, Department of Endocrinology,
urine albumin-to-creatinine ratio (UACR) ≥300 mg/g.
Singapore General Hospital
Canagliflozin reduced the risk of the primary composite
endpoint by 30 percent, defined by doubling of creatinine,
renal replacement therapy, and renal or CV death.
Importantly, the risk of end-stage kidney disease (ESKD)

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ARE OUR TYPE 2 DIABETES PATIENTS SUFFICIENTLY PROTECTED
FROM CARDIORENAL COMPLICATIONS?

was reduced by 32 percent, and risks of major adverse CV CURRENT CLINICAL INDICATIONS FOR
events and hospitalisation for heart failure (HHF) were also SGLT2 INHIBITORS
reduced.
1. Type 2 diabetes
In the DAPA-CKD10 trial, dapagliflozin reduced the primary
endpoint by 39 percent, resulting in a number needed to 2. Type 2 diabetes and albuminuric kidney disease
treat of 19, and benefits were independent of glycaemic (albuminuria of ≥200 mg/g of creatinine plus eGFR of
status. The risks of ≥50 percent eGFR decline and ESKD 25-90 ml/min per 1.73 m2)
were reduced by 47 percent and 36 percent, respectively. The 3. Nondiabetic albuminuric kidney disease (albuminuria
composite of CV death or HHF was reduced by 29 percent, ≥200 mg/d plus eGFR of 25-75 ml/min per 1.73 m2)
and overall mortality was reduced by 31 percent. There were 4. Type 2 diabetes with cardiovascular disease
no new safety signals reported in the DAPA-CKD10 trial – 5. Heart failure with reduced ejection fraction, with or
in particular, no imbalances related to fracture, amputation, without diabetes
diabetic ketoacidosis, or serious renal events.

It is heartening to note that the cardiorenal benefits seen ADDRESSING BARRIERS

with SGLT2 inhibitors are also reflected in real-world
evidence studies, which encompass more diverse patient Cost and medication access are commonly cited barriers.
characteristics and a close approximation of routine clinical Locally, this has been substantially ameliorated in the public
practice. sector with the entry of dapagliflozin and empagliflozin into
the Medication Assistance Fund scheme (MAF) thanks to
CVD-REAL2,6 a large observational study including
the onset of value-based pricing in 2017.
patients from Singapore, suggested that compared to other
glucose-lowering drugs, initiation of SGLT2 inhibitors was Clinical inertia is next. Jeong et al11 documented that
associated with a lower risk of death and HF in real-world SGLT2 inhibitors are underutilised for eligible patients
patients with T2D regardless of pre-existing CVDs. In both (eGFR of at least 45 mL/min/1.73 m2 and UACR of at
EMPRISE7 and CVD-REAL, a majority of patients did not least 30 mg/g): only 32.9 percent of patients were receiving
have established CVD or HF at baseline, suggesting that the drug treatment. The authors also observed that primary
SGLT2 inhibitors provide cardiorenal protection very early care doctors in South Korea were deferring the decision
on in the progression of CVD. to endocrinologists, adding to treatment delay. Globally,
cardiologists and nephrologists are now reframing their
EMPEROR-Reduced8 and DAPA-HF9 provided further
therapy focus, viewing SGLT2 inhibitors as agents with
convincing evidence that SGLT2 inhibitors, independent of
robust evidence for cardiovascular and renal benefits, rather
diabetes status and glycaemic effects, are highly effective and
than waiting for primary care or endocrinology to initiate a
well-tolerated therapies that reduce cardiovascular death/
glucose-lowering agent.
hypertensive heart failure (HHF) and improve quality of life
in HFrEF. The benefits of SGLT2 inhibitors on HFrEF were Fear of acute kidney injury also hinders drug initiation. In
similar in patients with and without diabetes, and extended reality, the initial decline in eGFR of up to 30 percent after
down to eGFR 20 ml/min/1.73m2. SGLT2 inhibitor initiation is likely due to a reduction in
intraglomerular pressure and actually reflects the desired
Topline results from the EMPEROR-Preserved Phase III
drug action. In the absence of hemodynamic instability,
trial were released in July 2021. These results showed that it
SGTL2 inhibitors do not increase the risk of acute kidney
met its primary endpoint or significant risk reduction with
injury (AKI). In fact, an overall reduction in AKI has been
empagliflozin for the composite of cardiovascular death or
observed with SGLT2 inhibitor use.12 It is also consistently
hospitalisation for heart failure in patients with heart failure
demonstrated that eGFR curves cross at 12-14 months, with
with preserved ejection fraction (HFpEF) – widening the
continued separation, emphasising the sustained benefits of
base of evidence for SGLT2 inhibitors in the spectrum of
staying on therapy.
heart failure.
Figure 1: The acute reversible reduction in eGFR
In the DAPA-CKD trial,10 dapagliflozin reduced the primary
with subsequent sustained benefits13
composite endpoint by 39 percent. The risks of ≥50 percent
eGFR decline and end-stage kidney disease (ESKD) were Supports long-term beneficial effect of
reduced by 47 percent and 36 percent, respectively. EMPA- treatment on eGFR slope
Kidney (ClinicalTrials.gov Identifier: NCT03594110) will
further fill a data gap around efficacy and safety in people
with lower eGFR and lower UACR.
Separation of Curves

Time from Randomisation

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 ARE OUR TYPE 2 DIABETES PATIENTS SUFFICIENTLY PROTECTED
FROM CARDIORENAL COMPLICATIONS?

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FROM CARDIORENAL COMPLICATIONS?

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LEARNING POINTS
• In heart failure trials for SGLT2 inhibitors, there is consistently demonstrated reduction in
cardiovascular death and hospitalisation for heart failure.
• In renal outcome trials for SGLT2 inhibitors, there is consistently demonstrated reduction in clinically
important hard renal endpoints.
• Tackling clinical inertia requires a multifactorial approach including timely updates of guidelines,
early adoption of effective therapies by clinicians, and shared decision-making with patients.

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